US4680267A - Fermentor control system - Google Patents

Fermentor control system Download PDF

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Publication number
US4680267A
US4680267A US06/707,363 US70736385A US4680267A US 4680267 A US4680267 A US 4680267A US 70736385 A US70736385 A US 70736385A US 4680267 A US4680267 A US 4680267A
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dissolved oxygen
medium
air
amount
sbsb
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US06/707,363
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Lee B. Eppstein
Robert D. Mohler
Shaul Reuveny
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New Brunswick Scientific Co Inc
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New Brunswick Scientific Co Inc
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Priority to US06/707,363 priority Critical patent/US4680267A/en
Assigned to NEW BRUNSWICK SCIENTIFIC COMPANY, INC. reassignment NEW BRUNSWICK SCIENTIFIC COMPANY, INC. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: EPPSTEIN, LEE B., MOHLER, ROBERT D., REUVENY, SHAUL
Priority to GB08603087A priority patent/GB2171818B/en
Priority to JP61038438A priority patent/JPH0779678B2/ja
Priority to DE3606449A priority patent/DE3606449C2/de
Priority to CH815/86A priority patent/CH669607A5/de
Priority to FR8602863A priority patent/FR2578266B1/fr
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/30—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration
    • C12M41/32—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration of substances in solution
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/26—Means for regulation, monitoring, measurement or control, e.g. flow regulation of pH
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/807—Gas detection apparatus

Definitions

  • the invention is generally directed to a control system for a tissue culture reactor and in particular to a control system for a tissue culture fermentor which exercises concurrent control of dissolved oxygen content (DO) and pH of a medium in a fermenting vessel containing a tissue culture fermentation.
  • Tissue culture fermenting vessels are used to grow cells attached to microcarriers or free suspension cell cultures in a liquid medium containing the various components needed for cell growth.
  • concentrations for certain materials are required. These variables include the acidity of the surrounding medium (pH), amount of dissolved oxygen (DO), as well as the concentration of other materials.
  • the liquid medium for culture growth is agitated by a stirrer, such as a magnetic stirrer, to maintain an even distribution of materials in the surrounding liquid and to attempt to prevent local accumulations of cells and the presence of concentration gradients which can produce undesirable effects upon the tissue culture cells.
  • a stirrer such as a magnetic stirrer
  • Cells from higher organisms growing in microcarrier cultures and free suspension cultures are relatively physically fragile and thus only low speed stirring is possible.
  • a significant potential of harmful concentration gradients is possible where liquid acids or bases are introduced to the fermenting vessel. This makes control of pH by other than addition of liquids extremely desirable, where possible.
  • tissue culture fermenting process As a tissue culture fermenting process operates, the oxygen and pH needs of the tissue culture change. As a result, there is a need to adjust the flow of materials into the fermenting vessel at various stages of the fermenting process to maintain the tissue culture cells in an optimal growth environment. In addition to maintaining the environmental conditions within ranges of acceptable values, a consistency of values is desired.
  • tissue culture cells are responsive not only to the environmental conditions present in the surrounding liquid, but to changes in the environmental conditions of the liquid medium. Therefore, the tissue culture cells often grow more efficiently in a less stressful environment where rapid changes in the surrounding environment are avoided. Therefore, rapid and repeated changes in the surrounding environment are to be avoided.
  • tissue culture fermentor control systems have independently monitored and controlled the level of dissolved oxygen (DO) and pH in the fermenting vessel.
  • DO dissolved oxygen
  • the present invention is generally directed to an apparatus for controlling the dissolved oxygen and pH of a culture medium during a bioreaction process such as fermentation, in a vessel.
  • a dissolved oxygen sensor generates a signal corresponding to the dissolved oxygen in the medium.
  • a pH sensor generates a signal corresponding the pH of the medium.
  • a valve member selectively applies air, N 2 , O 2 and CO 2 to the fermenting medium.
  • a controller produces a control signal for controlling the operation of the valve mechanism so that a substantially fixed volume of gas consisting of one or more of air, CO 2 , N 2 and O 2 is added to the medium during a period of time.
  • the controller determines in response to the dissolved oxygen and pH signal the amount of CO 2 , O 2 and/or N 2 required to effect the dissolved oxygen and pH correction.
  • the controller adjusts these determined values to compensate for the displacement of air as a result of CO 2 added so that the effect of the CO 2 correction on the dissolved oxygen is substantially minimized.
  • Another object of the invention is to provide an improved tissue culture fermentor conftrol system which reduces the need for constant and radical infusions of dissolved oxygen and carbon dioxide to maintain the environment within prescribed boundaries.
  • a further object of the invention is to provide a control system which simultaneously controls the amount of dissolved oxygen and the pH in a bioreactor.
  • Still another object of the invention is to provide a pH-dissolved oxygen control system for a tissue culture fermentor which uses time proportioned control of the flow of air, N 2 , O 2 , and CO 2 to maintain the pH and amount of dissolved oxygen within narrow ranges of values.
  • Another object of the invention is to provide a tissue culture fermentor control system which reduces the interaction of the independent outputs of the dissolved oxygen and pH controllers to minimize stressful changes to the medium.
  • the invention accordingly comprises the several steps and the relation of one or more such steps with respect to each of the others, and the apparatus embodying features of construction, combinations of elements, and arrangements of parts which are adapted to effect such steps, all as exemplified in the following detailed disclosure, and the scope of the invention will be indicated in the claims.
  • FIG. 1 is a front elevational view of a tissue culture fermenting system, including a control system constructed in accordance with a preferred embodiment of the invention
  • FIG. 2 is a block diagram of the functional elements in a tissue culture fermentor system constructed in accordance with the invention
  • FIG. 3 is a block diagram of a gas control system used in a preferred embodiment of the invention.
  • FIG. 4 is a flow diagram of the operation of a tissue culture fermentor control system constructed in accordance with the invention.
  • Fermentation system 10 includes a fermentation vessel 20 having a tissue culture and liquid medium 22 contained therein.
  • Vessel 20 contains a magnetically driven agitation system 24 rotatably supported on cover 25 for agitating medium and cell culture 22 in vessel 20.
  • a pH probe 26 extends into vessel 20 through cover 25 and is supported thereby.
  • pH probe 26 is implemented using glass electrode technology.
  • pH probe 26 can be of any type as long as it does not react with the medium or cell culture within fermentation vessel 20.
  • a dissolved oxygen (DO) probe 28 also projects into fermenting vessel 20 through cover 25 and is supported thereby.
  • DO dissolved oxygen
  • DO sensor 28 may be a galvanic or polarographic type DO sensor.
  • DO probe 28 is a galvanic type probe which produces a millivolt signal directly proportional to the rate of oxygen diffusion through its membrane.
  • a gas inlet 30 is provided for fermentation vessel 20 through the drive shaft 29 of agitation system 24, which is adapted to feed the added gases to the medium from near the bottom of the agitation system in a manner which produces substantial dissolving of the gases in the fluid without undue foaming.
  • any desired sparging system may be used.
  • An alkaline entry tube 31 also penetrates through cover 25 into vessel 20 to deliver a basic solution or other liquid into medium 22 when required.
  • Fermenting vessel 20 rests on a base 32 which rests on a main console 34.
  • the vessel is supported by a heater/support member 33.
  • Main console 34 includes a power switch 36 and houses a microprocessor 60 (FIG. 2).
  • a display console 38 sits on a stand 40 on top of main console 34.
  • Display console 38 includes a digital display 42 for depicting temperature and agitation values.
  • a flow meter 44 is present on the front of display console 38.
  • Main console 34 rests on top of an instrument console 46 which contains a digital display 48 for displaying the amount of dissolved oxygen and the pH of medium 22.
  • Instrument console 46 also has a series of switches 50, 52 and 54 for manually adjusting the set points of the controlled variables. Electrical connection between the sensors, such as pH probe 26 and DO probe 28, and the main console is provided (not shown).
  • the control system includes a microprocessor 60 which has a central processer unit as well as memory components including a RAM and a ROM (or an EPROM or EEPROM), to store set points, calibration information, programs, data and calculation results.
  • Microprocessor 60 receives inputs from pH probe 26 through a pH signal conditioner 62 and from DO probe 28 through a DO signal conditioner 64.
  • pH signal conditioner 62 and DO signal conditioner 64 convert the analog electrical signal received from probe 26 and DO probe 28, respectively, into a frequency signal through the use of an optical coupler to provide electrical isolation of the pH and DO signals from each other and from the microprocessor. Thereafter, the frequency signals indicative of the pH of the medium and of the DO are input into microprocessor 60.
  • the frequency inputs are multiplexed so as to enter microprocessor 60 in a single port. However, separate input ports may also be used.
  • Microprocessor 60 also receives user inputs from front panel controls 66 which include switches 50, 52 and 54 for adjusting the set points of the pH and DO levels.
  • Microprocessor 60 outputs signals to front panel display 68 which includes, among other front panel displays flow meter 44 and digital DO and pH display 48.
  • Microprocessor 60 outputs data recorded on microprocessor 60 which is indicative of the environmental state of the medium and cell cultures in fermentation vessel 20 during the period in which the fermentation process is going on to analog recorder outputs 70.
  • Analog recorder outputs 70 allow for a user of the fermenting system to analyze the environmental conditions of the fermentation process or other bioreaction over the life of the process, which can often extend to a period of days or several weeks. In this way, repeatability of a desired reaction can be achieved through emulation of the environmental guideposts of a successful process.
  • microprocessor 60 controls the operation of gas control valves 72.
  • Gas control valves 72 are coupled to sources of air, gaseous nitrogen (N 2 ), gaseous oxygen (O 2 ) and gaseous carbon dioxide (CO 2 ).
  • the output of gas control valves 72 are coupled to gas inlet 30 for introduction of the gases into fermentation vessel 20.
  • Microprocessor 60 outputs time variable signals indicative of time periods during which the flow of selected gases are to occur. However, in a preferred embodiment, microprocessor 60 does not output an air signal directly. Rafther, if microprocessor 60 indicates that no N 2 , O 2 or CO 2 is to flow into gas inlet 30, air is selected. This can be implemented with a series of inverters 77 and an AND gate 78. Gases are supplied from a source of N 2 73, source of O 2 74, source of CO 2 75 and source of air 76. The gas exiting valves 72 are connected to gas inlet 30 and introduced into fermentation vessel 20.
  • FIG. 4 wherein the cycle followed by microprocessor 60 in implementing the control over the fermentattion system is depicted.
  • Microprocessor 60 reads the front panel switches in block 120 and then reads the pH and DO values in block 140.
  • block 160 the current value and/or set point of the various variables are displayed on one of the displays on the front panel and output to analog recorder output 70.
  • the control outputs are calculated in block 180 which causes the appropriate flow of gases into fermenting vessel 20.
  • the data received is stored in a back-up memory unit in step 200 and the cycle repeats itself again beginning at block 120.
  • the present invention is directed to minimizing the interaction of the independent outputs of the DO and pH controllers which tend to counteract each other and results in relatively large variations in the state of the cell culture process, to the detriment of the process.
  • the interaction is minimized by using the outputs of DO and pH controllers as inputs to a gas flow controller.
  • pH probe 6 in association with pH signal conditioner 62 and DO probe 26 in association with DO signal conditioner 64 act as the DO and pH controllers respectively.
  • Microprocessor 60 in this embodiment acts as the gas flow controller which implements its gas flow decisions by sending signals to gas control valve 72.
  • Microprocessor 60 performs several functions to act as a gas flow controller. First, it generates positive outputs ⁇ N 2 and ⁇ O 2 which are functions of the current error and all previous errors in DO (except in certain cases described below). In addition, microprocessor 60 generates continuous positive outputs ⁇ CO 2 and ⁇ ALK which are functions of the current error and all previous errors in pH.
  • the various " ⁇ " functions are calculated (calculated as described below) from two terms: one term being a term proportional to the present error and the other term being related to an integration of the errors present in the process from its beginning until the present.
  • the error is defined as the difference between the current value of a variable and its set point.
  • the set point is set by an operator by use of front panel controls 66. The set point may be adjusted during the course of the fermentation process by the user. However, it remains the same unless so changed.
  • the " ⁇ " variable is calculated as follows:
  • K c is a scaling constant used to adjust the value of " ⁇ ” based on the capacity of the medium and the length of the gas cycle.
  • ⁇ represents the error, which is equal to the difference between the current value and the set point.
  • t m is a system constant which is representative of the time between measurements of the error.
  • t m is equal to one second. This results in the conversions being asynchronous to the process, thereby reducing the delay between the measurement and the corrective action to about one second.
  • ⁇ is the time constant for the integrated term.
  • K c , t m and ⁇ are preset and are not user accessible. However, in another embodiment they may be altered by the user.
  • ⁇ is the sum of the errors measured over the period that the process has been operating.
  • the " ⁇ " functions have both a proportional term and an integrated term which attempt to approximate the current demand of the system for the particular variable input.
  • ⁇ there are, however, certain constraints on the calculation of ⁇ as defined by the above equation. If the sum of the proportional and integration term is too large, representative of the process starting far from the set point, preset limits are imposed on ⁇ and the integration is stopped to prevent the carrying through of large corrections where it may provide a destabilizing impact on the process.
  • the proportional term has a maximum value for each variable and if the proportional term exceeds this value, ⁇ is limited to this upper value and the integration term is reset to zero.
  • the purpose of the upper value of the proportional term is to prevent over-compensation and dangerously high gradients of input which are particularly stressful to the tissue culture cells. Under such circumstances, the control scheme waits until the tissue culture process is closer to the set point and then starts the above-described control system as if the process was just starting.
  • microprocessor 60 generates time proportional outputs t air , t N .sbsb.2, t O .sbsb.2 and t CO .sbsb.2 which control the gas flow into the reactor.
  • the gas flow controller operates on the basis of a cycle during which there are two phases. During one phase air is input into fermenting vessel 20 and during the other phase of the cycle one or more of N 2 , CO 2 and O 2 in specified volumes are added to fermentation vessel 20. In a preferred embodiment t cycle is equal to two seconds. The cycle time can be varied depending upon the speed at which the fermentation process or other bioreaction proceeds the computing power and memory available and the degree of control desired.
  • ⁇ N .sbsb.2, ⁇ O 2 , ⁇ CO .sbsb.2 and ⁇ ALK are positive continuous outputs which are functions of the current error and an estimate of the demand for that variable based on the history of the variable. Only one of ⁇ N .sbsb.2 and ⁇ O .sbsb.2 will be positive and only one of ⁇ CO 2 and ⁇ ALK will be positive. These positive outputs are utilized to control the relative quantity of each of the gasses during each cycle.
  • the volume of gas introduced into fermentation vessel 20 during a cycle 20 is substantially constant within the physical limitations of gas valves 72. As a result, the following equation is used to represent the amount of each of the gasses input into the fermenting vessel during a cycle.
  • t air represents the time during the cycle when air is input into the fermentation vessels.
  • the relative values of t air t O .sbsb.2, t CO .sbsb.2 and t N .sbsb.2 are determined as follows. If ⁇ O .sbsb.2 is greater than zero, then:
  • the effect of the added CO 2 required for pH correction on the D0 correction is compensated for.
  • the system compensates for the amount of air displaced by the CO 2 .
  • the system compensates for the amount of air displaced by the CO 2 by adding air (reduces N 2 ) or adding oxygen, the N 2 and C0 2 being considered equal inert gases for this purpose.
  • the final situation is one in which, where ⁇ N .sbsb.2 and ⁇ O .sbsb.2 are equal to zero and, then;
  • a second example is where the pH controller requires 100 ms. of CO 2 and the DO controller requires 250 ms. of N 2 .
  • t CO .sbsb.2 100 ms.
  • t N .sbsb.2 150 ms. ( ⁇ N .sbsb.2 - ⁇ CO .sbsb.2).
  • the N 2 is added by the DO controller to increase the amount of inert gas added instead of oxygen and for the purposes of the DO controller it is not important whether the 250 ms. of inert is all N 2 or a combination of N 2 or CO 2 by adjusting the proportion of inert between N 2 and CO 2 in this case, both the DO and pH control requirements can be met.
  • the third example is where the pH controller requires 100 ms. of CO 2 and the DO controller requires 50 ms. of N 2 .
  • the DO controller only requires 50 ms. of inert gas but the pH controller requires 100 ms. of CO 2 (and inert gas with reference to the DO controller). Therefore, an additional 50 ms. of inert CO 2 is added which displaces the oxygen which would have been added to the 50 ms. of air displaced.
  • Microprocessor 60 may, after determining the values of t O .sbsb.2, t CO .sbsb.2 and t N .sbsb.2 calculates the value t air based on the known constant value of t cycle for any predetermined cycle time. With all four gas times now calculated, the appropriate signals can be sent to gas control valve 72 to send an appropriate amount of the various gases into fermenting vessel 20. However, in the embodiment of FIG. 3, this air calculation is unnecessary as the system defaults air in the absence of an instrument to feed O 2 , N 2 or CO 2 .
  • the gas flow controller is implemented in a preferred embodiment as software associated with microprocessor 60.
  • the software is implemented in a read only memory (ROM, PROM, EPROM, or EEPROM) chip.
  • ROM read only memory
  • PROM PROM
  • EPROM EPROM
  • EEPROM electrically erasable programmable read-only memory
  • the software may be implemented utilizing bubble memory or some other type of non-volatile storage medium.
  • Gas control valves 72 in a preferred embodiment, are implemented as four solonoid valves.
  • One of the solenoid valves is a three way valve which switches a single outlet between an "air” or a “mixture” flow.
  • the other three valves control the N 2 , O 2 and CO 2 sources into the mixture input of the three-way valve.
  • the user may also elect to remove the fermentation system from the control mode in which the gas flows are controlled and convert the fermentation system to a second mode where only air is inputted into the fermentation vessel.
  • the present invention has been described with respect to a fermentation process for a tissue culture medium.
  • the controller is equally applicable to a hollow fiber process and a glass bead packed column process. All of these processes can be considered bioreactions.
  • a pH-DO control system particularly adapted for a tissue culture fermentation process which serves to prevent unstable variations in pH and DO during a fermentation reaction by coupling the control of these two variables.

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US06/707,363 1985-03-01 1985-03-01 Fermentor control system Expired - Lifetime US4680267A (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US06/707,363 US4680267A (en) 1985-03-01 1985-03-01 Fermentor control system
GB08603087A GB2171818B (en) 1985-03-01 1986-02-07 Control of dissolved oxygen and ph
JP61038438A JPH0779678B2 (ja) 1985-03-01 1986-02-25 媒体の溶存酸素及びｐＨ制御方法及び装置
DE3606449A DE3606449C2 (de) 1985-03-01 1986-02-27 Fermenter-Steuersystem
CH815/86A CH669607A5 (enrdf_load_stackoverflow) 1985-03-01 1986-02-28
FR8602863A FR2578266B1 (fr) 1985-03-01 1986-02-28 Procede et dispositif pour controler un fermenteur.

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US (1) US4680267A (enrdf_load_stackoverflow)
JP (1) JPH0779678B2 (enrdf_load_stackoverflow)
CH (1) CH669607A5 (enrdf_load_stackoverflow)
DE (1) DE3606449C2 (enrdf_load_stackoverflow)
FR (1) FR2578266B1 (enrdf_load_stackoverflow)
GB (1) GB2171818B (enrdf_load_stackoverflow)

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USD370263S (en) 1994-10-12 1996-05-28 Heraeus Instruments Gmbh Bioreactor
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US5888805A (en) * 1996-05-30 1999-03-30 Rikagaku Kenkyusho Detecting apparatus for monitoring culture broth in bio-reactor
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EP1710298A1 (de) * 2005-04-04 2006-10-11 Leo Kübler GmbH Automatisches Gärsystem und Gärkontrolle
US20060275858A1 (en) * 2005-06-02 2006-12-07 Saucedo Victor M Optimization of Process Variables in Oxygen Enriched Fermentors Through Process Controls
US20080064076A1 (en) * 2006-09-11 2008-03-13 Saucedo Victor M Dissolved Oxygen Profile to Increase Fermentation Productivity and Economics
US20080182309A1 (en) * 2006-08-21 2008-07-31 Emtech, Llc Method and apparatus for magnetic fermentation
DE102009048113A1 (de) 2009-10-02 2011-04-07 Kurt-Schwabe-Institut für Mess- und Sensortechnik e.V. Meinsberg Sensorgestütztes Mikroreaktorsystem
US9835370B2 (en) 2014-09-16 2017-12-05 Eppendorf Ag Freezer, in particular ultra-low temperature freezer
US10017789B2 (en) * 2015-03-25 2018-07-10 The Board Of Regents For Oklahoma State University System and method for feedback control of gas supply for ethanol production via syngas fermentation using pH as a key control indicator
US10190084B2 (en) 2009-07-06 2019-01-29 Genentech, Inc. Method of culturing eukaryotic cells
CN109796230A (zh) * 2019-02-27 2019-05-24 北京农业智能装备技术研究中心 好氧发酵装置及其使用方法
WO2019230433A1 (ja) * 2018-05-28 2019-12-05 エイブル株式会社 ｐＨセンサのコンディショニング方法、培養装置、及び、培養制御装置

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JPH0191771A (ja) * 1987-10-01 1989-04-11 Sumitomo Electric Ind Ltd 細胞増殖装置
IL88937A0 (en) * 1989-01-12 1989-08-15 Mordechai Zisser Method of manufacturing feed for livestock and poultry
KR0132666B1 (en) * 1989-03-14 1998-04-14 Hitachi Kk Method for controlling cultivation conditions for animal cells
DE3927856A1 (de) * 1989-08-23 1991-02-28 Bat Cigarettenfab Gmbh Verfahren zur prozessfuehrung mindestens eines bioreaktors fuer pflanzliche zellkulturen
US5656421A (en) * 1990-02-15 1997-08-12 Unisyn Technologies, Inc. Multi-bioreactor hollow fiber cell propagation system and method
DE4037325A1 (de) * 1990-11-23 1992-05-27 Karl Mueller U Co Kg Verfahren zur erzeugung von zellmasse und/oder fermentierungsprodukten unter sterilen bedingungen sowie vorrichtung zur durchfuehrung des verfahrens
US5426024A (en) * 1992-10-23 1995-06-20 Centro De Investigacion Y De Estudios Avanzados Del Instituto Politecnico Nacional Fermentation method and fermentor
JP4740138B2 (ja) 2003-10-10 2011-08-03 ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト 真核生物細胞におけるポリペプチドの大規模生産方法及びそれに適した培養容器
CN110451626A (zh) * 2019-09-02 2019-11-15 泉州师范学院 中小尺度养殖水体中溶解氧和pH精确控制的装置及方法
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JPH0779678B2 (ja) 1995-08-30
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FR2578266B1 (fr) 1989-11-24
JPS61202684A (ja) 1986-09-08
CH669607A5 (enrdf_load_stackoverflow) 1989-03-31
GB8603087D0 (en) 1986-03-12
GB2171818B (en) 1988-10-19
FR2578266A1 (fr) 1986-09-05
DE3606449C2 (de) 1996-02-08

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